Abiraterone acetate, the chemical name of which is (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate of formula (1), is the prodrug of the active metabolite abiraterone (2), a selective inhibitor of enzyme CYP17.

Abiraterone acetate forms the basis of the novel medicament Zytiga®, a tablet formulation containing 250 mg of active ingredient, which is administered orally at a single daily dose. When combined with prednisone or prednisolone it is indicated for the treatment of metastatic, castration-resistant prostate cancer in adult males in whom the disorder appears during or after a chemotherapy regimen based on docetaxel.
Numerous processes are reported in the literature for the preparation of abiraterone or derivatives thereof. In most cases the starting product is prasterone (dehydroepiandrosterone).
The preparation of abiraterone acetate was originally disclosed in EP0633893. Its synthesis involves conversion of the carbonyl at the 17 position of dehydroepiandrosterone-3-acetate (prasterone acetate, 3) to the corresponding enol triflate (4) by treatment with trifluoromethanesulphonic anhydride and 2,6-di-tert-butyl-4-methylpyridine (Scheme 1).

The triflate intermediate is purified by chromatography on silica and then precipitated by crystallisation from hexane. The pyridine ring is introduced by Suzuki reaction between said triflate and diethyl(3-pyridyl)borane to obtain crude abiraterone acetate (1), which is purified by chromatography on silica, eluting with a mixture of ethyl ether and petroleum ether, and finally crystallised from hexane.
The use of bases which are more common and cheaper than 2,6-di-tert-butyl-4-methylpyridine is claimed in patent application WO2006/021777. The use of said bases also limits the formation of an impurity deriving from the elimination of the ester group at the 3 position, although the formation reaction of intermediate (4) is incomplete, and the crude abiraterone acetate obtained after the Suzuki reaction contains appreciable amounts of dehydroepiandrosterone-3-acetate (3). Said crude product can be purified by salification of (1) with acids, in particular with methanesulphonic acid, in tert-butyl methyl ether, as claimed in WO2006/021776; however, the purity of the methanesulphonate salt thus obtained is not very high, even after recrystallisation from isopropyl alcohol (purity of crude product <90%, purity of purified product about 96%), and yields are globally modest. Similar purifications by salification have formed the object of publications and/or patent applications, e.g. via sulphate (IPCOM000211139D), phosphate (CN102731605), oxalate (CN103059090) or trifluoroacetate (WO2013/123878).
Patent application WO2013/053691 claims the preparation of abiraterone (2) using, instead of prasterone acetate (3), the corresponding formate (5). Similarly to the sequence described above for (3), formate (5) is converted to triflate (6) and then to abiraterone formate (7), which is hydrolysed under basic conditions to obtain abiraterone (2). The latter can then be acetylated to abiraterone acetate (1) (Scheme 2).

An alternative process for the preparation of abiraterone acetate is disclosed in EP0721461 (Scheme 3).

The key intermediate of said process is 17-iodo-androsta-5,16-dien-3β-ol (10), obtained in two steps from dehydroepiandrosterone (prasterone, 8) through hydrazone (9). The Suzuki reaction between vinyl iodide (10) and diethyl(3-pyridyl)borane leads to the formation of abiraterone (2), which is then acetylated to give abiraterone acetate (1).
Evaluation of the methods used to synthesise abiraterone (2) and abiraterone acetate (1) as described in the prior art demonstrates that none of said methods seem to have optimum characteristics in terms of yield, purity, workability, cost, and implementability on an industrial scale.
In many cases, impurities are formed which are difficult to remove, such as those listed below; triene (11) and the 3,5-cyclo derivative (12) are specific to synthesis via triflate, and due to impurities that accompany triflates (4) and (6), which are typically used as crude products instead of carrying out expensive chromatographic purifications on silica.

Moreover, the limited stability of said crude triflates 4 and 6 or the solutions thereof strongly influences the possibility of storage, and has an adverse impact on the planning and output of the manufacturing facility.
Preparation of abiraterone acetate (1) can also require an acetylation step, which is necessary in cases wherein the synthesis uses abiraterone (2) as precursor, such as in WO2013/053691 and WO95/09178, and also in syntheses that use prasterone acetate (3) as starting material, for example as reported in IPCOM000211139D. The acetylation processes described are unsatisfactory in terms of the complexity of the operations and/or the yields.
When the purification methods described in the prior art are used, it is very difficult to eliminate the impurities present completely; moreover the procedures are laborious, and losses are very high.
The discovery of a process that obviates the drawbacks illustrated above would therefore be highly desirable.